Though their name implies something novel, new approach methodologies (NAMs) have been used for drug development and chemical testing for decades. Pharmaceutical and chemical companies along with contract research organizations (CROs) routinely employ NAMs to meet international regulatory requirements, often substituting them for traditional animal models where scientifically appropriate.
What opportunities are now available for developers who want to integrate alternative, non-animal approaches into their research programs, and what scientific and regulatory challenges stand in the way of fully replacing animal models?
NAMS in practice
In recent years, the global regulatory landscape has begun to shift in favor of non-animal testing strategies. Several jurisdictions and international bodies have already taken concrete steps to recognize or require the use of validated NAMs. For example, Europe and Canada have passed laws prohibiting the use of live animals in cosmetics testing. The Organisation for Economic Co-operation and Development (OECD) has approved a range of in vitro and in silico study designs for skin sensitization, endocrine disruptors, developmental neurotoxicity, and inhalation toxicology that have replaced the need for animals.
More recently, advanced in vitro methodologies, including 3D human tissue models, cell-based protein arrays, organoids, and organs-on-a-chip, have been developed to reshape the NAMs field for biomedical research. These alternative models are transforming discovery research, enabling developers and chemical manufacturers to answer critical go/no-go questions that previously relied almost exclusively on animal studies. The use of NAMs is crucial for derisking future safety studies and supporting the industry’s ongoing commitment to the 3Rs framework of replacement, reduction, and refinement of animal use.
However, in the highly regulated toxicology testing environment, where studies assess the impact of pharmaceuticals and chemicals on human health and the environment, NAMs are still rarely used as full replacements for animal models. The human system is incredibly complex, with 78 organs working in harmony — making it challenging for alternative approaches to fully replicate systemic interactions.
NAMS opportunities and challenges in the nonclinical realm
Virtual Control Groups (VCGs) are a novel approach currently being explored to reduce the number of animals used in toxicology studies. Broadly defined, VCGs consist of datasets derived from control animals in previous studies, which can then serve as substitutes for live control animals in subsequent experiments.
Numerous VCG pilot projects, like the one launched in 2024 at Charles River Laboratories with Sanofi, are leveraging years of legacy data to gauge how these “virtual” controls compare to their “live” animal counterparts in toxicology studies. However, before VCGs can be widely adopted, critical prerequisites must be addressed, including standardized data collection and curation, robust statistical evaluation, and a clear validation strategy. These measures are essential to ensure study outcomes remain reliable and that human risk assessments are not compromised, according to a recent report authored by 19 scientists.
Another promising area for NAMs in the US regulatory space is cosmetic ingredient testing. Since 2013, Europe has prohibited the sale of any cosmetics tested on animals, with Canada implementing a similar ban in 2023. The US is increasingly moving in the same direction, creating new opportunities for the development and adoption of alternative testing approaches.
The FDA’s Modernization of Cosmetics Regulation Act of 2022 (MoCRA) expanded the agency’s authority over beauty and cosmetic safety by requiring manufacturers to provide proof of safety substantiation for their products. The updated legislation also includes a non-binding recommendation to phase out animal testing for cosmetic ingredients. Currently, there are approximately 784,000 cosmetic products listed with the FDA, many of which have yet to undergo safety testing since the passage of MoCRA. By leveraging in vitro testing methods already approved in Europe, developers can evaluate the ingredients in existing products and also help to shape NAMs’ regulatory acceptance in the US.
Immunogenicity testing is another opportunity for the development of NAMs. In toxicology studies of biological therapeutics, a common endpoint is assessing whether these products trigger unwanted immune responses. Developing a validated, regulatory-accepted in vitro NAM assay to measure immunogenicity could be a powerful tool for predicting the safety of therapeutics in humans.
Progress but also challenges in the short and long-term
There are many more alternative methods in various stages of development, ranging from liver chips for genotoxicity studies, organoids, spheroids, artificial intelligence (AI) models, to emerging approaches in reproductive toxicology, a field long reliant on animal studies for assessing drug safety. At the World Organoid conference held in Cambridge in 2024, keynote speaker Thomas Hartung reported that AI had predicted the toxicity of over 4,700 food chemicals with 87 percent accuracy in one hour, which would have otherwise required the use of 38,000 animals.
Meanwhile, microfluidic systems that better replicate the three-dimensional architecture of human tissues are becoming increasingly sophisticated. In 2023, a team of researchers from Cortical Labs, Monash University, the University of Melbourne, and University College London demonstrated that a brain organoid could process an input and produce a measurable, learned response to stimuli — the first step toward creating in vitro models for neurodevelopmental and degenerative disorders in a dish.
Still, it is essential not to let hype outpace science. The near future of drug development will still depend on blending the strengths of traditional animal models with cutting-edge alternatives, and some studies will likely always require the use of whole animals. Animal models have long served as the backbone of nonclinical testing, offering systemic insights that are difficult to replicate in vitro. They provide valuable data on pharmacokinetics, biodistribution, and immune responses — aspects where NAMs still face limitations.
In this rapidly evolving landscape, where emerging technologies and refinements to existing methods are advancing at pace, the industry faces the ongoing challenge of identifying the most effective approaches for evaluating tomorrow’s drugs. While regulators and the public are eager to embrace a future increasingly shaped by NAMs, it is essential for laboratories charged with testing new drugs or chemicals to manage expectations.
Skin irritation studies, one of the most basic adverse effects to model in vitro, took more than two decades for the OECD to adopt as a validated test guideline and 30 years for an integrated assessment approach to be developed and implemented. For more complex and long-term endpoints, validated in vitro assays that are reliably predictive of animal outcomes do not currently exist. Adding to this challenge is the difficulty of communicating these scientific complexities to the public. Many consumers struggle to grasp why developing safe, effective, and scientifically robust alternatives can take time, particularly when the goal is to match or exceed the reliability of traditional animal models.
Fortunately, there is considerable effort within industry and government to accelerate this process in a meaningful and responsible manner. The Validation and Qualification Network, an initiative of the Foundation for the National Institutes of Health, is bringing together industry and regulators to help get the most promising NAM technology across the regulatory finish line.
Ultimately, the most crucial question for the industry and regulators to address is not strictly about phasing out animals but whether we can enhance clinical outcomes. Right now, nine out of every 10 drug candidates fail in the clinic due to safety or efficacy concerns. As we enter a new era of technology, our focus should be on those patients and developing methods that ensure that those other nine drugs succeed, whether it is in an animal, a NAM, or a mix of both.
